1. Field of the Invention
This invention relates to an emulsion composition for delivering highly water-soluble drugs such as vinca alkaloids.
2. Description of the Related Art
Despite years of research into the development of more effective and safe therapeutic agents for cancer, cancer drugs remain extremely toxic to patients. The common systemic toxicities associated with cancer drugs, such as chemotherapeutic agents, include bone marrow suppression, asthenia, peripheral neuropathy, dyspnea, alopecia, etc. To make things worse, many intravenously injected cancer drugs can cause local reactions at the injection site resulting in vein irritation, pain, tissue necrosis and/or thrombophlebitis. The consequence of injection site reactions to a chemotherapy agent may include extreme pain, early termination of drug treatment, wounds that are difficult to heal, scars, permanent tissue damage, and, in the worst case, amputation.
Alkaloids isolated from the periwinkle plant (Vinca rosea) and derivatives thereof, collectively referred to as “vinca alkaloids,” have proven effective as first line therapy for many types of lymphomas, leukemias, and other cancers. Vincristine and vinblastine consist of a catharanthine moiety linked to vindoline, and the structures differ by a single substitution in the vindoline group. Vindesine, a desacetyl carboxyamide derivative of vinblastine, was synthesized later. Subsequently, novel synthetic approaches were used to generate compounds that differed from the natural compounds by the presence of an eight- rather than a nine-member catharanthine ring, including vinorelbine, which is commonly available as a tartrate salt, i.e., vinorelbine bitartrate or vinorelbine tartrate.
Vinca alkaloids are highly cytotoxic drugs that disrupt microtubules, inhibit cell division and induce apoptosis. Without wishing to be bound to a particular theory, it is believed that vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of microtubules.
Vincristine, vinblastine and vinorelbine are the best-known members of this drug family and are widely used clinically. Despite having similar structures and mechanisms of action, vinca alkaloids differ in their antitumor activity and toxicities. For example, vincristine is used mostly to treat hematological cancer, and neurotoxicity is dose limiting. In contrast, vinorelbine is approved for the use as a single agent to treat breast and non-small cell lung cancer, and its injection site reaction is most severe amongst all vinca alkaloid drugs.
It is well known that all vinca alkaloid drugs are associated with adverse reactions at the injection site. For example, the current vinorelbine product approved in the U.S. (NAVELBINE®) has a “blackbox” warning due to its severe reaction at the injection site.
NAVELBINE® is reportedly associated with a high incidence (51%-61%) of local reactions at the injection site, characterized by injection site pain and phlebitis. The injection site reaction or extravasation of NAVELBINE® can be severe, ranging from considerable pain, irritation, and tissue necrosis to thrombophlebitis (The NAVELBINE® Product Information by GlaxoSmithKline).
NAVELBINE® (vinorelbine tartrate) is a simple solution formulation for intravenous administration. Each vial contains vinorelbine tartrate equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in water for injection at pH 3.5.
Rittenberg reported post-incident care and management of venous irritation or phelibitis due to NAVELBINE® (Oncol. Nurs. Forum 22: 707-10, 1995). Mare reported methods for preventing venous toxicity of NAVELBINE® by co-administering anti-inflammatory drugs as defibrotide or ketorolac, or changing infusion schedules from a bolus infusion to a slow infusion (Support Care Cancer 11: 593-6, 2003). However, the injection site toxicity problem of vinorelbine or other vinca alkaloids has not been properly addressed from the drug formulation approach and vinca alkaloid products remain the most venous toxic drugs.
Oil-in-water emulsion formulations may provide advantages over a traditional solution formulation such as the one used by NAVELBINE® in control of venous toxicity at injection site for irritating drugs. For example, the intramuscular or intravenous injection of erythromycin or clarithromycin in a solution formulation causes severe pain at the injection site, and erythromycin or clarithromycin fat emulsion (oil-in-water) is locally non-irritating (WO 90/14094). However, oil-in-water emulsion formulations are typically applied to only lipophilic drugs such as propofol, diazepam, erythromycin or clarithromycin, etc. Desai (U.S. Pat. No. 4,816,247) disclosed emulsion compositions for administration of sparingly water soluble ionizable hydrophobic drugs.
Without wishing to be bound to a particular theory, it is believed that in an oil-in-water emulsion, a lipophilic drug is preferentially dissolved in the oil phase and therefore is coated and/or encapsulated in the oil droplets, thus preventing direct contact of drug molecules at a high concentration with the venous endothelium tissue, thus reducing the venous toxicity of the drug.
However, to date, the utility of an emulsion in preventing venous toxicity of irritating drugs is limited to only lipophilic (or hydrophobic) drugs since highly water-soluble drugs, such as vinca alkaloid drugs, do not partition well in the conventional emulsion oil droplets. For example, vinorelbine in the bitartrate salt form is highly soluble in water with an aqueous solubility is >1000 mg/mL in distilled water.
Thus, there remains a need in the art for developing compositions for delivering highly water soluble drugs. The present invention fulfills such a need and provides other related advantages.